Gastrointestinal (GI) motility is a coordinated neuromuscular process which transports nutrients through the digestive system. Impaired GI motility, can lead to irritable bowel syndrome, constipation and diabetic and post-surgical gastroporesis and is one of the largest health care burdens of industrialized nations. Motilin, a 22 amino acid prokinetic peptide is expressed throughout the gastrointestinal tract in a number of species including humans. Released from endochromafffin cells of the small intestine, motilin exerts a profound effect on gastric motility with the induction of interdigestive (phase III) antrum and duodenal contractions. The unrelated macrolide antibiotic erythromycin also possesses prokinetic properties mediated by its interaction with motilin receptors. These account for erythromycin's GI side-effects, including vomiting, nausea, diarrhea and abdominal muscular discomfort.
Motilin receptors have been detected in the GI tract and recently in the central nervous system, but their molecular structure has not been reported. Although motilin receptor characterization has been actively pursued in humans and other species since the isolation of motilin from porcine intestine in 1972, the receptor itself has not been isolated nor cloned.
Motilin is highly conserved across species and is synthesized as part of larger pre-prohormone. Mature 22 amino acid motilin is generated by removal of its secretory signal peptide and cleavage at the first C-terminally located dibasic prohormone convertase recognition site. Using radioligand binding, autoradiography and in vitro biossays, high affinity and low density, motilin receptors were detected in smooth muscle cells of the gastrointestinal tract of humans, cats and rabbits. Cerebellar brain receptors for motilin were also described supporting the notion that motilin may act in the central nervous system. Native motilin receptors appear to be coupled to G proteins and activate the phosphlipase C signal tranduction pathway resulting in Ca2+ influx through L-type channels.
The development of safe and selective motilin receptor agonists is likely to aid the treatment of disorders resulting from impaired GI motility. Thus, it would be desirable to be able to isolate, and clone the motilin receptor, and to use this in assays for agonists and antagonists.